The Development of Granules Based on Arginine and Ginseng

Kateryna Romas, Natalya Polovkо, Liliia Vyshnevskа, Olga Antonenko

National University of Pharmacy, Kharkiv, Ukraine.

*Corresponding Author E-mail: romas.k.1983@gmail.com

ABSTRACT:

The objective of the work is to develop the composition and technology of granules based on arginine and ginseng. Methods. Physical, chemical and technological methods have been used. Results. After preliminary determination of L-Arginine properties, it was found that it has poor flowability. To improve technological properties, it was necessary to select an auxiliary substance. It was found that the most suitable excipient is lactose monohydrate. In order to avoid additional stages of the manufacturing process when tincture of ginseng roots was introduced into the mixture, it was decided to use it as a granulating liquid. Obtained granules showed the best result of flowability, but there was a pronounced heterogeneity in the shape and size of the granules. Necessary was the introduction of granulating liquid binders, as which 5 % alcohol solution of polyvinylpyrrolidone was chosen. In order to prevent excessive wetting of the mass as a solvent to obtain a 5 % solution of polyvinylpyrrolidone, we used ethanol 70 % and a tincture of the ginseng root. Obtained granules are grains of round, cylindrical and irregular shape, homogeneous in color, with a specific odor, sweet taste. Conclusions. Based on technological, physical and chemical researches we developed a rational technology of granules for the treatment of cerebrovascular diseases. Auxiliary substances and the granulation method were selected. Technological properties of granules were studied. Quality indicators were determined, expiration dates and conditions for their storage were set.

KEYWORDS: Technology, granules, arginine, ginseng, cerebrovascular diseases.

L-Arginine is a conditionally indispensable amino acid, which is a necessary precursor for the synthesis of many biologically significant molecules (ornithine, proline, polyamines, creatine, and agmatine). Arginine takes part in the regulation of the endocrine glands work, pancreas and pituitary gland; it is the donor of the molecule of nitric oxide (NO), which in turn has a wide spectrum of bio regulatory effects, in particular modulation of the vascular system^2-5.

Ginseng (Panax ginseng, Araliaceae family) - is widely known in medicine and pharmacy due to pronounced tonic and stimulating properties in mental and physical fatigue and weakness. In addition, the ginseng root has immunomodulating and restorative activity, which is due to the presence in its composition of a large number of biologically active substances (triterpene glycosides, mucus, resins, and vitamins B1, B2, C, choline, bitter, essential and fatty oils, pectins, carbohydrates and others)^6,7.

The objective of the work is to develop the composition and technology of granules based on arginine and ginseng. The choice of this dosage form was because the granules are convenient to use, have good bioavailability, easy manufacturing and storage stability.

Methods. The preparation of granules was carried out by the conventional wet granulation method. Auxiliary substances, namely granulating (binding) liquids, which determine the quality of the granulated material and the granules themselves (strength, disintegration, dissolution), play an important role in granulation. The requirement for the granulated mass is its plasticity and the absence of sticking properties. The resulting granules were analyzed and standardized to determine storage conditions and shelf life.

The disintegration test for granules was carried out on the identifier of the disintegration process DT-1000 (LabIndia, India) (“swinging bucket”, medium – purified water, medium’s volume – 1000ml, temperature – (37.0 ± 2.0)°C, speed of rotation – (30±2) cycles/min.

The strength of the abrasion of the granules was determined using a drum tester of friability and abrasion AE1 (Labline, Austria).

Flowability was determined using an automated powder testing facility PTG-S4 (Pharma Test, Germany), according to the pharmacopoeia procedures EuPh <2.9.36>, USP <1174> and ISO 4324.

The fractional composition was determined by means of a vibration shaker BA 200N (CISA, Spain), the moisture content using the moisture analyzer OHAUS MB-35 (Switzerland).

RESULTS AND DISCUSSION:

After a preliminary experimental determination of the pharmacological properties of the substance L-Arginine, it was found that it has poor flowability. To improve the technological properties, it was necessary to select an auxiliary substance, which makes it possible to obtain a homogeneous bulk mass. To this end, the possibility of using potato starch, lactose monohydrate, magnesium oxide and glucose was studied. Mixtures of these substances with L-Arginine were prepared in various ratios.

As a result, it was found that the most suitable excipient is lactose monohydrate (FlowLac-100) in the ratio 1:1. Moreover, the addition of lactose allowed not only to improve the technological characteristics of the mixture for granulation, but also the organoleptic properties, namely, to disguise the unpleasant taste of the granules, due to the presence in their composition of the amino acid L-Arginine with bitter taste.

In order to avoid additional stages of the manufacturing process when tincture of ginseng roots was introduced into the mixture, it was decided to use it as a granulating liquid. The obtained granules showed the best result of flowability, but there was a pronounced heterogeneity in the shape and size of the granules, which is also indicated by large fluctuations between the bulk volume and the volume after shaking. Necessary was the introduction of granulating liquid binders.

We studied water solutions of starch (5%), methylcellulose (3%), aqueous and alcoholic solutions of polyvinylpyrrolidone (5%), often used together with tincture of ginseng root. The granulation mass was prepared by moistening the mixture of L-Arginine and lactose with the liquids listed above to obtain a plastic homogeneous mass.

None of the mixtures obtained, with the exception of polyvinylpyrrolidone, moistened with alcohol solution, did not have satisfactory technological properties. All of them were viscous, sticky and granulation was not possible.

When trying to reduce the amount of binding fluid, the mass was not molded. We hypothesized that this is due to the high degree of ability of the mixture of L-Arginine and lactose to form aqueous solutions, as well as its hygroscopicity. Consequently, the use of aqueous solutions of high-molecular compounds in this case is inappropriate. As a result, 5% alcohol solution of polyvinylpyrrolidone (solvent - ethanol 70 %) was chosen as the binding liquid.

In order to prevent excessive wetting of the mass as a solvent to obtain a 5 % solution of polyvinylpyrrolidone, we used ethanol 70 % and a tincture of the ginseng root in a ratio of 1:9. The use of this humidifier promoted the production of the granules, the technological indicators of which corresponded to the established norms.

Due to the ability of the substance polyvinylpyrrolidone to form water-soluble complexes, there was an improvement in the solubility of the granules and, therefore, increased bioavailability of the active substances.

The technology of the granules was as follows: previously sieved lactose and L-Arginine were mixed until homogenous, gradually added with constant rapid mixing of the humectant until a plastic mass was obtained.

The resulting wet granules were dried in a drying oven at a temperature of 50-60°C, then sieved to separate small and large fractions and packed in sealed containers of dark glass.

Based on the conducted studies, a technological scheme for the preparation of granules was proposed (Fig. 2).

The obtained granules are grains of round, cylindrical and irregular shape, homogeneous in color (cream), with a pleasant slightly expressed specific odor, sweet taste. Very soluble in water.

The results of physical, chemical and technological studies of the granules based on L-Arginine and tincture of ginseng root are presented in Table 1.

As can be seen from the presented data in Table 1, the developed granules meet the requirements for this dosage form for the indicated quality indicators.

Table 1. The results of determining the main quality indicators of the granules based on the amino acid L-Arginine and the tincture of the root of ginseng

Series No.	Appearance (description)	Fractional composition of the granules, %			Humidity, %	Disintegration time, min.	Flowability, g/sec	Mechanical strength, %
Series No.	Appearance (description)	Less 0.2 mm	0.2 - 3.0 mm	more 3.0 mm	Humidity, %	Disintegration time, min.	Flowability, g/sec	Mechanical strength, %
010416	Grains of round, other forms, cream color	1.5±0.03	97.3±0.05	1.2±0.06	8.03±0.05	7.8±0.05	11.8±0.06	98.51±0.65
020416	Grains of round, other forms, cream color	1.8±0.07	97.6±0.04	0.6±0.03	8.13±0.04	8.4±0.06	12.0±0.05	99.50±0.56
030416	Grains of round, other forms, cream color	1.1±0.04	98.2±0.05	0.7±0.02	8.50±0.06	7.3±0.02	12.5±0.07	98.83±0.72
040416	Grains of round, other forms, cream color	1.4±0.05	98.1±0.03	0.5±0.04	8.73±0.04	7.1±0.07	12.1±0.08	99.16±0.74
050416	Grains of round, other forms, cream color	1.6±0.02	98.0±0.03	0.4±0.01	8.62±0.03	8.2±0.03	12.2±0.04	98.78±0.61

Fig. 2. Technological scheme for the production of the granules based on arginine and ginseng

Table 2. The results of studying the stability of the main quality indicators of the granules based on the amino acid L-Arginine and the tincture of the root of ginseng

Series No.

Duration of storage (months)

Moisture contents, %

Disintegration time, min.

Mechanical abrasion resistance, %

010416

8.40

8.04

8.21

8.16

8.19

7.9

7.8

8.0

8.2

8.4

98.6

98.8

99.0

99.1

98.9

020416

8.27

8.20

8.11

8.07

8.42

8.0

8.5

8.2

7.8

7.7

98.7

99.2

99.0

99.1

99.0

030416

8.15

8.07

8.01

8.33

8.28

8.1

7.7

7.9

8.6

8.2

99.2

99.3

98.7

99.4

98.9

040416

8.41

8.22

8.08

8.13

8.25

8.3

8.4

8.0

7.9

7.8

98.8

99.0

99.2

98.7

98.6

050416

8.14

8.17

8.25

8.26

8.39

8.4

7.7

7.8

8.3

8.0

99.4

99.0

99.4

99.3

98.7

Control of the stability of granules during storage was carried out by studying disintegration time, moisture content and mechanical strength. Analyzed five series of the medicine placed in containers of lightproof glass and stored in a dry place at room temperature (Table 2).

Based on the results obtained, the shelf life of the granules is determined to be 2 years. During this period, the granules remain stable over all the studied parameters.

CONCLUSIONS:

The composition and technology of the granules based on the amino acid L-Arginine and the tincture of the ginseng root were developed. The auxiliary substances and the granulation method were selected. The technological properties of granules were studied. A technological scheme for the production of the granules based on the amino acid L-Arginine and tincture of the root of ginseng was developed. Quality indicators of the developed granules were determined, expiration dates and conditions for their storage were set.

CONFLICT OF INTERESTS:

The authors claim that there is no conflict of interest.

REFERENCES:

1. Gandzyuk V.A. Dynamics of morbidity and prevalence of circulatory system diseases among the population of Ukraine at the present stage: national and regional aspects. Bulletin of Social Hygiene and Organization of Public Health of Ukraine. 2014; 2 (60): 74-78.

2. Almakaeva L.G., Litvinova E.V. Arginine and its application in medicine and pharmacy. Medicines of Ukraine. 2011; 1 (5): 23-26.

3. Gage S.L., Nighorn A. The role of nitric oxide in memory is modulated by diurnal tim. Front. Syst. Neurosci. 2014; 8: 59.

4. Rushaidhi M., Jing Y., Kennard J.T., Collie N.D., Williams J.M., Zhang H., Liu P. Аging affects L-arginine and its metabolites in memory-associated brain structures at the tissue and synaptoneurosome levels. Neuroscience. 2012; 3: 21-31.

5. Yi J., Horky L.L., Friedlich A.L., Shi Y., Rogers J.T., Huang X. L-arginine and Alzheimer’s disease. Int. J. Clin. Exp. Pathol. 2009; 2: 211-218.

6. Buntsevich L.L., Ageeva N.M., Kostyuk M.A. Cultivation of ginseng in culture in vitro, development of drinks with the use of its extracts. Fruit growing and viticulture. 2014; 30 (6): 33-44.

7. Choi K.T., Meyer C.A. Botanical characteristics, pharmacologic al effects and medicinal components of Korean Panax ginseng. Acta Pharmacol. Sin. 2008; 29: 1109-1118.

Received on 20.02.2020 Modified on 05.04.2020

Research J. Pharm. and Tech. 2020; 13(11):5370-5374.

DOI: 10.5958/0974-360X.2020.00939.7